Intermediates for tricyclic amines

ABSTRACT

1-Chloro- or 1-fluoro- derivatives of 5H-dibenzo(a, d)cycloheptenes and 1-chloro- or 1-fluoro- derivatives of 10,11dihydro-5H-dibenzo(a,d)cycloheptenes having, at position 5, a basic exocyclic side chain of the formula   wherein R1 is hydrogen or methyl, and intermediates therefor are prepared by alternate procedures. The described end-products are useful, for example, as psychopharmacological antidepressants.

United States Patent 11 1 Kyburz et al.

[ INTERMEDIATES FOR TRICYCLIC AMINES [75] Inventors: Emilio Kyburz, Reinach; Hans Spiegelberg, Basel, both of Switzerland [73] Assignee: Hofimann-La Roche Inc., Nutley,

[22] Filed: Mar. 8, 1974 21 Appl. No.: 449,319

Related US. Application Data [60] Division of Ser. No. 107,499, Jan. 18, 1971, abandoned, which is a continuation-in-part of Ser. No. 679,644, Nov. 1, 1967, abandoned.

[56] References Cited UNITED STATES PATENTS 3,527,806 9/1970 Bellet et al 260/471 C Nov. 4, 1975 Primary ExaminerAnton H. Sutto Assistant Examiner-L. A. Thaxton Attorney, Agent, or FirmSamuel L. Welt; Bernard S. Leon; William G. lsgro [57] ABSTRACT l-Chloroor l-fluoroderivatives of 5l-l-dibenzo[a,dlcycloheptenes and l-chloroor l-fluoroderivatives of l0,l l-dihydro-5H-dibenzo[a,d]cycloheptenes having, at position 5, a basic exocyclic side chain of the formula wherein R, is hydrogen or n'iethyl, and intermediates therefor are prepared by alternate procedures. The described end-products are useful, for example, as psychopharmacological antidepressants.

1 Claim, No Drawings INTERMEDIATES FOR TRICYCLIC AMINES This is a division, of application Ser. No. 107,499 filed Jan. 18, 1971, now abandoned which in turn is a continuation-in-part application of Ser. No. 679,644, filed Nov. 1, 1967, now abandoned.

BACKGROUND OF THE INVENTION 5H-Dibenzo[a,d]cycloheptenes and 10,1-l-dihydro- SH-dibenzo [a,d]cycloheptenes havingv a basicside chain in the 5-position for example, 10,1 l-dihydro-S- (3-dimethylaminopropylidene )-5l-ldibenzo[a,d]cycloheptene (amitriptyline) and 10,11- dihydro-5-( 3 -methylaminopropylidene )-5l-l-dibenz0[a,d]cycloheptene (nortriptyline, are known for their psychopharrnacological antidepressant properties.

The compounds of this invention of hereinafter described formulas Ia and lb, which differ from the prior art compounds by the presence of a chlorine or fluorine at position-l, unexpectedly exhibit substantially increased antidepressant activity and significantly decreased toxicity. Also, they show a substantial absence of anticholinergic activity. Anticholinergic activity is not desirable in psychopharmacological antidepressant 2 compounds, and its absence is particularly advantageous. Additionally, the compounds of formulas la and lb are characterized by their action on the nervous systems, for example, they possess narcosis potentiating, adrenolytic, sedative, antihistaminic and local anesthetic activities.

BRIEF DESCRIPTION OF THE INVENTION This invention relates to novel derivatives of 5H- dibenzo [a,d]cycloheptenes useful as psychopharmacological anti-depressant agents and to novel intermediates useful inthe preparation thereof. In particular, the invention relates to psychopharmacological antidepressant tricyclic amines of the formulas and wherein R is chlorine or fluorine, R is hydrogen or methyl, R and R are hydrogen, chlorine or fluorine, and X is ethylene, vinylene or halo-substituted vinylene, and the pharmaceutically acceptable acid addition salts thereof. The compounds of formulas la and lb and their pharmaceutically acceptable salts are useful, for example, as pyschopharmacological antidepressants.

DETAILED DESCRlPTlON OF THE INVENTION This invention relates to tricyclic amines of the formulas and alkyl denotes a straight chain or branched chain alkyl' group containing 1-7 carbon atoms, e.g., methyl, ethyl, propyl, isopropyl, butyl, pentyl, hexyl and the like.

Unsymmetrically substituted compounds of formula Ib, which have an exocyclic double bond in the -position, form geometric isomers which hereinafter will be referred to as the aor the B-isomer. This invention includes all the geometric isomers of the compounds of formula lb whether they be obtained as mixtures or as an individual isomer. The isomers of the compounds of formula lb exhibit psychopharmacological antidepressant activity as well as the other activities mentioned hereinbefore, and are particularly useful as psychopharmacological antidepressants.

unsymmetrically substituted compounds of formula Ia form optical isomers. These isomers as well are included in the invention. They show the same useful activities as indicated hereinbefore.

A preferred subgenus of the compounds of formula la is represented by the formula wherein R is hydrogen or methyl, R and R are hydrogen, chlorine or fluorine, and X is ethylene, vinylene or halo-substituted vinylene, and pharmaceutically acceptable acid addition salts thereof.

A more preferred subgenus comprises a compound of formula wherein R and R are hydrogen.

A preferred subgenus of the compounds of formula lb is represented by the formula wherein R is hydrogen or methyl, R and R are hydrogen, chlorine or fluorine, and X is ethylene, vinylene, or halo-substituted vinylene,

5 and'pharmaceutically acceptable acid addition salts thereof.

A more preferred subgenus comprises a compound of formula Id wherein R and R are hydrogen.

Compounds of this invention corresponding to formulas la and lb are exemplified by the following:

l-chloro-l0,l l-dihydro-5-( 3-methylaminopropyl)- 5H-dibenzo[a,d]cycloheptene; l-chloro-5-(3-dimethylaminopropylidene)-5H- dibenzo[a,d]cycloheptene;

the B-isomer of l-chloro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene; l-chloro-5-(3-methylaminopropylidene)-5H-dibenzo[a,d]cycloheptene; the B-isomer of l-chloro-5-(3-methylaminopropylidene)-5H-dibenzo[a,d]cycloheptene; l-chloro-10,l l-dihydro-5-(3 dimethylaminopropyl)- 5H-dibenzo[a,d]cycloheptene; l-chloro-l0,l l-dihydro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene; the B-isomer of l-chloro-l0,ll-dihydro-5-(3-dimethylaminopropylidene)-5H- dibenzo[a,d]cycloheptene; l-chloro-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene; l-fluoro-10,1 l-dihydro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene; 1-fluoro-l0,l l-dihydro-5-(3-dimethylaminopropyl)- 5H-dibenzo[a,d]cycloheptene; l-chloro-lO (or 1 l )-bromo-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene; 1,10 (or 1 l )-dichloro-5-(3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene; l,3-dichlorol 0,1 l-dihydro-5-( 3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene; the B-isomer of l,3-dichloro-l0,l l-dihydro-5-(3- dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene; l,3-dichloro-l0',l l-dihydro-5-(3-dimethylaminoprop'yl)-5H-dibenz'o[a,d]cycloheptene; and l,9-dichloro-l0,l l-dihydro-5-(3-dimethylaminopropylidene)-5 H-dibenzo[a,d]cycloheptene. The tricyclic amines of the invention can be prepared utilizing several alternate processes for example:

1. A compound of the formula Y CH wherein R, R R R and X are as previously described and one of Y or Y is hydrogen and the other is hydroxy,

can be reduced or dehydrated to form the corresponding compound of formulas la or lb;

2. A compound of the formula wherein R, R R and X are as previously described and W is halogen, I 5 can be reacted with a dimethylaminopropyl magnesium {ialide to fonn the corresponding compound of formula 3. A compound of the formulae wherein R, R R and X are as described above, Z is halogen or a substituted sulfonyloxy residue, and A is the anion of an acid,

can be treated with methyla'mine or dimethylamine to form the corresponding compound of formulas la or lb;

4. A primary amine of the formula CHz-CHz- CHz-Z lVa wherein R, R R and X are as previously described,

can be methylated to form the corresponding compound of formulas la 0%: lb; 5. A compound of the formula Vllla wherein R, R R and X are as previously described,

can be debenzylated to form the corresponding compound of formulas la or lb; 6. compound ofthe formula wherein R, R R and X are aspreviously described,

and T is an alkali-metal atom, such as sodium, potassium and the like, can be reacted with acompound of the formula Vlllb wherein L is a halogen or a substituted sulfonyloxy residue, to form the corresponding compound of formula la; or

L5 8. A compound of the formula 1 Xll whelifi Rf'RflRs andfX are as Pr v y s ribed,

and D is acyl or anesterified carboxyl,

can be hydrolyticall'y c'leav ed, whereupon, -if desired, in

optional sequence, if a monomethylamino compound is obtained, it can 'be methylated; if a dimethylamino compound is obtained, it can be converted by demethylation into a monomethylamino compound; if a product with an unsubstituted ethylene or vinylene group X is obtained, this group can be converted into a halogenated vinylene group; if a l0,l l-dihydro-compound is obtained, itjcan be dehydrogenated. Furthermore, if desineduthe geometric or bptical isomers can be iso- 40 lated fromfan isomeric mixture obtained, and a base obtained can be'fconye'rted into a salt.

According to a preferred embodiment of a process of the invention, a carbinol of general formula ll is reduced or dehydrated. Preferred starting substances are compounds of formula I] wherein Y is a hydroxyl and Y 'is hydrogen. The reduction of compounds of formula ll leads to exocyclically saturated compounds of formula la. The reduction may be conveniently carried out with a nascent hydrogen produced by reacting, for

example, zinc. in glacial acetic. Another very suitable reducing agent is hydroiodic acid; By treatment of a compound-of--formulafi II with hydrloiodicacid, espe cially in the. presence" of red phosphorus, the compounds of formula la whichare saturated in the 10,1 1-

5 position, are easily obtained. In conducting the reduction, it is preferred to work inthe presence of a solvent, such as, acetic acid or acetic acid anhydride, at a temperature in the range of room temperature and the boiling point of the reaction mixture.

The dehydration of compounds of formula II leads to compounds of formula lb, having an exocyclic double ybond in the 5-position. This dehydration is convenie ntly carried out using a mineral acid, such as, hydrochloric or hydrobromic acid, in which case the dehydration can be carried out in an anhydrous or an aqueous medium. The dehydration is preferably carried out in ethanolic hydrochloric acid at a temperatuare in the range of room temperature and the boiling point of the reaction mixture. However, dehydration can also be accomplished utilizing heat, for example, at 50C. to reflux temperature, preferably at reflux temperature, with a high-boiling anhydrous solvent, such as, dimethyl sulfoxide. Other known dehydrating agents can also be employed, for example, acetyl chloride, acetic acid anhydride, trifluoroacetic acid anhydride, sulfuric acid, phosphorus oxychloride, p-toluenesulfonyl chloride, zinc chloride, potassium bisulfate, or the like. An inert organic solvent, such as chloroform, methylene chloride, or the like, can be employed at a temperature in the range of room temperature and the boiling point of the reaction mixture.

The carbinol of formula ll can be prepared by known procedures, for example, by reaction of the corresponding tricyclic S-ketone with suitable Grignard compounds. The tricyclic ketones of the formula wherein R, R R and X are as previously described, can be prepared by methods known per se (see e.g. J. Med. Chem. 8(6) 1965 These methods are also illustrated in Examples 9, l l, 12, 13 and 15 hereinafter. It is to be noted that the introduction of a halogen atom into the 10 (or 1 l)-position of l-chloro (or fluoro)-5H- dibenzo[a,d]cyclohepten-S-one is preferably effected by addition of the desired halogen with simultaneous irradiation. After addition of an alkali, the resulting lchloro (or fluoro)-l0,l l-dihalo.-l0,l l-dihydro-SH- dibenzo[a,d]cyclohepten-5-one splits off one molecule of hydrogen halide, whereby the l-chloro (or fluoro)- 10 (or l1)-halo-5H-dibenzo[a,d]cyclohepten-5-one is obtained.

Carbinols of formula ll wherein Y, is hydroxyl and Y is hydrogen are conveniently obtained as follows:

When a carbinol of formula ll wherein R, is methyl is to be prepared, the corresponding tricyclic S-ketone is reacted directly with, for example, dimethylaminopropyl magnesium chloride, and the reaction product is subsequently hydrolyzed. If R, is hydrogen, it is preferred to use methyl-benzyl-aminopropyl magnesium chloride as the reagent for the reaction. After complete reaction and subsequent hydrolysis, the resulting product is reacted with ethyl chloroformate to form 5- hydroxy-S 3-( methyl-c arbethoxy-amino )-propyl] compound which is hydrolyzed, whereupon a spontaneous decarboxylation occurs with the concurrent formation of the corresponding 5-hydroxy-5-(3- methylaminopropyl) compound.

Carbinols of formula 11, wherein Y, is hydrogen and Y is hydroxyl are obtained, for example, by reacting a corresponding tricyclic S-ketone with ethyl magnesium bromide and hydrolyzin g the reaction product. The resulting S-hydroxy-S-ethyl compound is dehydrated with acetyl chloride and, subsequently, treated with formic acid and hydrogen peroxide. The 5-hydroxy-5-( 1- hydroxyethyl) compound which forms is dehydrated with aqueous sulfuric acid to yield the corresponding 5acetyl compound. By treatment with formaldehyde and methylor dimethylamine hydrochloride, there is obtained a S-(methylor dimethylaminopropionyl) compound which, after reduction with sodium borohydride, yields the corresponding carbinol.

According to another embodiment of a process of the invention, a halide of formula 111 is reacted with a dimethylaminopropyl magnesium halide to form the corresponding exocyclically saturated compound of formula la. This process is particularly suitable for the preparation of those exocyclically saturated compounds of formula la which simultaneously carry a double bond in the 10,1 l-position. Preferably, a compound of formula 111 wherein W is chlorine, in a solid, finely powdered form or in an organic solvent, such as, for example, absolute ether, benzene, tetrahydrofuran, or the like, is introduced into a suspension of dimethylaminopropyl magnesium chloride in one of the solvents mentioned hereinbefore. The reaction is conveniently carried out at a temperature in the range of room temperature and the boiling point of the reaction mixture. After complete reaction, the reaction product is subjected to hydrolysis, preferably under practically neutral conditions, for example, by treatment with aqueous ammonium chloride solution.

The starting halide of formula "I can be prepared ac cording to known methods, for example, by the reduction of the corresponding tricyclic 5-ketone and subsequent halogenation of the resulting S-hydroxy compound.

A further embodiment of a process of the invention comprises treating a compound of general fomiulas IVa, lVb, Va, Vb or V1 with methylamine or dimethylamine. ln the above formulas [Va and lVb, Z preferably is a chlorine or bromine atom. The substituted sulfonyloxy residues, as a meaning for Z, are preferably lower alkyl-sulfonyloxy residuies, such as mesyloxy; phenylsulfonyloxy residues; lower alkylphenylsulfonyloxy residues, such as tosyloxy; or phenyl-(lower alkyl)-sulfonyloxy residues, such as phenylmesyloxy. The anion A is preferably derived from an inorganic acid, such as, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid or the like.

The reaction of methylor dimethylamine with a compound of formulas IVa or lVb, especially those wherein Z is halogen, represents a preferred process of the invention.

The reaction of compounds of formulas IVa, lVb, VA, Vb or V1 with methylor dimethylamine is conveniently carried out in a closed vessel at elevated temperature, preferably in the range of about -l75C. The reaction can be effected in an inert organic solvent, such as methanol, ethanol, benzene, toluene or the like. Preferably, the reaction is conducted in the presence of an excess of methylor dimethylamine. In the case of reaction of compounds of formulas IVa and lVb, the excess amine serves as an acid-binding agent. Other acid-binding agents, such as, anhydrous potassium carbonate, can also be employed. The compounds of formula VI are preferably reacted in the presence of a metal, such as, for example, sodium or lithium, a metal amide, such as, for example, sodium or potassium amide, or a metal-organic compound, such as, for example, phenyl-lithium or a Grignard compound. Particularly advantageous is the use of a Grignard compound.

The starting compounds of formulas [Va and lVb can be prepared, for example, by Yeaction of the co'llesponding tricyclic S-ketone with iflthoxypropyl ma nesium halide, subsequent hydrolyl leductioii Bf Hehydration of the resulting carbinol, and treatment of the dehydrated product with a halogenating agent. The quaternary salts of formulas Va and Vb, which can also be employed as the starting material, can be obtained by quatemization of the corresponding amino, monomethylamino or dimethylamino compound with a methylating agent, such as methyl chloride, methyl bromide, methyl iodide, dimethyl sulfate, or the like. The starting compound of formula VI is obtainable, for example, from the corresponding tricyclic S-ketone by reaction with an allyl Grignard compound.

According to another process of the invention, a primary amine of formulas VIIa or Vllb is methylated. The methylation can be carried out by treatment with a known methylating agent, such as, for example, methyl iodide, methyl tosylate, dimethyl sulfate, or the like, preferably at a temperature in the range of 1575C. According to another procedure, a mixture of formaldehyde and formic acid, preferably in excess, is reacted with a primary amine of formulas VIIa or VIIb at an elevated temperature in the range of about 50C. and the boiling point of the reaction mixture.

A preferred process for the preparation of secondary amines of formulas Ia or lb comprises reacting the corresponding primary amine of formula VIIa or VIIb with a haloformic acid ester, such as, for example, chloroor bromoformic acid ethyl ester, to form a carbamate, and, subsequently, reducing the carbamate with a metal hydride, such as, lithium aluminum hydride, diisobutyl aluminum hydride, or the like. Both reaction steps are preferably carried out in an inert solvent, for example, ether, tetrahydrofuran, or the like, at a temperature in the range of about room temperature and the reflux temperature of the reaction mixture, preferably at reflux temperature.

According to another process for the preparation of secondary amines of formulas Ia or Ib, a primary amine of formulas VIIa or Vllb is reacted with chloral, preferably in an inert solvent, such as chloroform, benzene, or the like, at an elevated temperature in the range of about 50C. and the .boiling point of the reaction mixture. The resulting formylamino compound is reduced to the secondary amine corresponding to formulas Ia or Ib with a metal hydride, such as, lithium aluminum hydride, in anhydrous ether.

Still another process for the preparation of secondary amines of formulas Ia or Ib comprises the reaction of a primary amine of formulas VIIa or VIIb with formaldehyde, preferably in an inert solvent such as benzene, toluene, and the like, at a temperature in the range of about room temperature and theboiling point of the reaction mixture. The resulting Schiffs base is subsequently converted into the corresponding secondary amine of formulas Ia or Ib by reduction. This reduction is conveniently effected with a metal hydride, such as, sodium borohydride or lithium aluminium hydride, in anhydrous ether or dioxane.

The starting compounds of formulas VIIa and VIII) can be obtained in several ways. The amiriopropylidene compounds of formula Vllb are obtained, for example, by exchange of the keto group of the corresponding 5- ketone with an ethylidene group, for example, by means of Grignard, and subsequent halogenation, treatment with a cyanide, and hydrolysis. The aminopropyl compounds of formula VIIa are conveniently prepared by reaction of the corresponding S-methoxypropyl or 5-methoxypropyl-5-hydroxy compound with hydrogen iodide, treatment of the resulting iodopropyl compound first with potassium phthalimide and, subsequently, with hydrazine.

According to a further process of the invention, compounds of formulas VIIIa or Vlllb are debenzylated. In the debenzylation, the benzyl group bound to the nitrogen atom is exchanged for a hydrogen atom, to yield the corresponding secondary amine of formula Ia or Ib. This reaction is conveniently carried out by reduction with an alkali metal, such as, for example, sodium or lithium, in liquid ammonia. In the debenzylation procedure, the double bonds which are present are substantially retained.

The starting compounds of formulas VIIIa and VlIIb are conveniently obtained by the reaction of the corresponding compound of formulas IVa, IVb, Va, Vb or VI with methylbenzylamine.

A still further process of the invention comprises the treatment of a compound of formula IX with aqueous acid at elevated temperature, resulting in the dehydration of the carbinol of formula IX. The substituent Q is simultaneously removed and there results the corresponding secondary amine of formulas Ia or Ib. In formula IX, Q preferably is the residue of an aromatic aldehyde, such as, for example, benzylidene or the like. The residue B preferably is the anion of a strong inorganic or organic acid, such as, for example, hydrochloric acid, sulfuric acid, methanesulfonic acid, benzenesulfonic acid, or the like, particularly preferred is the anion of toluenesulfonic acid.. According to a preferred embodiment, a compound of formula IX, wherein P is hydroxyl and P is hydrogen, is reacted with aqueous sulfuric acid at a temperature in the range of about 50l50C.

The starting compound of formula IX is obtained, for example, by reacting the corresponding S-hydroxy-S (3-aminopropyl) compound (prepared by reacting the corresponding S-ketone with an alkali-metal and treat ment of the resulting alkali-metal compound with an aminopropyl halide), a corresponding 5-(3-amino-lhydroxypropyl) compound (prepared by reacting the corresponding S-acetyl compound with formaldehyde and ammonium chloride, followed by reduction with sodium borohydride) or a compound of formulas VIIa or VIIb with an aldehyde, such as, for example, benzaldehyde and quatemizing the resulting Schiffs base with a known methylating agent, such as, methyl chloride, dimethyl sulfate, methyl mesylate, methyl benzenesulfonate or the like; particularly preferred is methyl tosylate, at an elevated temperature. The compound of formula IX which is obtained can be utilized without further purification. Often, it is advantageous not to isolate it, but immediately to allow the reaction mixture to react with the aqueous acid at an elevated temperature as discussed above.

A further process of the invention comprises the reaction of a compound of formula X with a compound of formula XI to form the exocyclically saturated compounds of formula Ia. In fonnula X, the symbol T preferably is sodium, potassium or lithium. L in formula XI is preferably chlorine. In its significance as a substituted sulfonyloxy residue, L preferably is a lower (cycIo-) alkylsulfonyloxy residue, such as, mesyloxy or cyclopropylsulfonyloxy; the phenylsulfonyloxy residue; a' lower alkylphenylsulfonyloxy residue, such as, tosyloxy; or a phenyl-(lower alkyl)-sulfonyloxy residue,

such as phenylmesyloxy. The reaction is conveniently carried out in an inert solvent such as benzene, toluene, hexane, heptane, ether or the like, at a temperature in 13 the range of about the room temperature and the boiling point of the reaction mixture.

The starting compound of formula X can be obtained, for example, by the treatment of the corresponding S-ketone or S-hydroxycompourid with aluminum isopropoxide, and subsequent reaction with an alkali-metal amide or hydride.

According to a still further process of the invention, compounds of general formula Xll are hydrolytically cleaved to yield the corresponding secondary amines of formula la. The group D can be, for example, acyl, such as, a lower alkanoyl group, for example, formyl or acetyl; a phenyl-(lower alkanoyl), for example, benzoyl; a lower alkylsulfonyl, for example, mesyl; phenylsulfonyl; lower alkylphenylsulfonyl, for example, tosyl; or phenyl-(lower alkyl)-sulfonyl, for example, phenylmesyl. The group D, in its significance as an esterified carboxy group, preferably is lower carbalkoxy, for example, carbomethoxy, carbethoxy or carboisopropoxy; carbophenoxy; or lower carbophenylalkoxy, for example, carbobenzoxy. When D is a non-sulfur-containing group, the cleavage proceeds under the conditions which are employed for acidic or alkaline hydrolysis, for example, with heating, for example, at a temperature in the range of about 50C. and the boiling point of the reaction mixture, in the presence of an ethanolic solution of hydrochloric acid, acetic acid, sodium hydroxide or potassium hydroxide. Alkaline hydrolysis is preferred. When D is a sulfur-containing group, it is preferred to conduct the cleavage by treatment with, for example, hydrobromic acid in acetic acid in the presence of phenol, an alkali-metal, such as sodium,

action is conveniently carried out in an inert solvent,

ssuch as, for example, benzene, ether, tetrahydrofuran, methylene chloride or the like, at a temperature beand a high-boiling alcohol, such as, butanol or hydroi- V odic acid and phosphonium iodide. Such reactions are conveniently effected with heating, for example, at a temperature in the range of about 50C. and boiling point of the reaction mixture. Another method for the cleavage of sulfur-containing group comprises treatment with liquid ammonia and an alkali-metal, such as, sodium.

The starting compound of formula Xll can be obtained, for example, by heating a compound of formula X in ether with a methyl-D-aminopropyl halide, wherein D is as described above.

The compounds of formulas la and lb, prepared as described above, can, if desired, be subjected to additional transformations.

A methylamino compound of formulas Ia or lb can be transformed into a dimethylamino compound according to known methods, for example, by treatment with a methylating agent, such as methyl iodide, methyl mesylate, methyl tosylate, dimethylsulfate or the like,

preferably at a temperature in the range of about l575C. According to another procedure, a mixture of formaldehyde and formic acid, preferably in excess, at an elevated temperature, for example, in the range of about 50C. and the boiling point of the reaction mixture, is reacted with the methylamino compound of fortween room temperature and the boiling point of the mixture. The resulting N-cyano-N-methylamino compound is subsequently hydrolyzed in a known manner in alkaline or acidic medium, whereby the monomethylamino compound of formulas la or lb is formed as a base or acid addition salt, depending on the hydrolysis medium employed.

According to another process for the demethylation of dimethylamino compounds of formulas la or lb, said compounds are treated with a haloformic acid ester and the resulting carbamate is hydrolyzed. The alco-- holic portion of the haloformic acid ester to be employed is preferably derived from an alcohol, such as, a lower alkanol, for example, methanol, ethanol, or isopropanol; phenol; or a lower phenyl-alkanol, for example, benzyl alcohol. The halo portion preferably is chlorine. The reaction with the haloformic acid ester is conveniently effected in a high-boiling inert solvent, such as, xylene or toluene, at a temperature in the range of about 50C. and the reflux temperature of the reaction mixture, preferably at reflux temperature. The subsequent hydrolysis can be carried out under alkaline or acidic conditions, for example, with potassium hydroxide in butanol or hydrogen bromide in glacial acetic, at a temperature in the range of about 50C. and the boiling point of the reaction mixture.

Unsubstituted groups X-,-i.e. the ethylene group, X and the vinylene group X, can, be converted into a halogen substituted vinylene group. By treatment with e.g. gaseous chlorine, preferably in an inert solvent such as carbon tetrachloride and with the application of light, two chlorine atoms are addedto'the unsubstituted vinylene group X. The temperature is not critical but is preferably kept between room temperature and the boiling point of the reaction mixture. The ethylene group X can be treated with an excess of a halogenating agent such as N-bromosuccinimide, N-chlorosuccinimide, bromine, chlorine or sulphuryl chloride, whereby two hydrogen atoms in 10,1 l-position are replaced by two halogen atoms. This reaction is preferably effected in an inert solvent such as carbon tetrachloride, benzene, heptane, chloroform or tetrahydrofuran and at elevated temperature, e.g. at 50C to the boiling point of the reaction mixture. It is very advantageous to add a small amount of a reaction; initiator such as azo-bisbutyronitrile or dibenzoyl peroxide, as well as a hydrogen halide acceptor, e.g. pyridine, triethylamine, collidine, allyl chloride or an epoxide. By treatment of a soobtained 10,1 l-dihalogen- 10,1 l-dihydro compound with an inorganic or organic base, for instance caustic soda, potassium carbonate or triethylamine, one molecule of hydrogen halide is split off yielding compounds of the formulas la or lb with ahalogen substituted vinylene group in 10,11-position. The temperature for this purpose is not critical but is preferably maintained between room temperature and the boiling point of the reaction mixture.

10,11-Dihydro compounds of the formulas la or lb can be dehydrogenated in the 10,1l-position. This is conveniently effected by heating e.g. at l50250C with a catalyst such as palladium carbon, Raney-nickel or platinum dioxide, conveniently in an inert solvent According to another mode of dehydrogenation I protecting group present there is obtained an amine, of

the formulas la or lb which is unsaturated in 10,11- position. 1

Representative examples of suitable protecting,

groups are: thecyanide. group or an esterified carboxy group, such as, carbomethoxy, carbethoxy, carboisopropoxy, carbophenoxy and carbobenzoxy. The cyanide group is conveniently introduced through reaction with a cyanogen halide, preferably with cyanogen bromide, for example, in an inert solvent, such as benzene, ether, tetrahydrofuran or methylene chloride, at a temperature in the range of about room temperatureand the boiling point of the reactionmixture'. The introduction of .the esterifiedcarboxy group is effected, for example, through reaction with the corresponding haloformic acid ester, such as, the chloroformic acid ester. This reaction is preferably effected in an inert solvent, such as, for example," chloroform, xylene, toluene or the like, at a temperature in therange of about room temperature and the boiling point of the reactionmixture. When a monomethylamino compound of formulas la or Ibis employed for the introduction of the cyanide group or of an esterified carboxy group, it is recommended to add an acid-binding agent, such as triethylamine, pyridine or the like. The reaction then proceeds quickly, and often at room temperature,

Another protecting group which can be suitably introduced into a monomethylamino compound of formulas Ia or lb is the acyl group derived from a lower carboxylic acid, such as, acetyl, isobutyryl, benzoyl,

phenylacetyl or the like. The introduction of such a protecting group is effected, for example, by the reaction of amonomethylamino compound of formulas la or Ib with acetyl chloride or aceticanhydride, conveniently in the presense of an acid-binding agent, such as, triethylamine, pyridine or the like. The reaction can be effected at a temperature in the range of about room temperature and the reflux temperature of the reaction mixture; room temperature is often sufficient.

' The 10,11-dihydro compound which may be protected at the nitrogen atom is subsequently treated with a halogenating agent, such as, N-bromosuccinimide, N-chlorosuccinimide, bromine, chlorine sulfuryl chloride or the like, whereby one or two hydrogen atoms are replaced by one or two halogen atoms in the 10- and/or ll-position, depending on the amount used of halogenating agent. The reaction is preferably effected in an inert solvent, such as, carbon tetrachloride, benzene, heptane, chloroform, tetrahydrofuran or the like at elevated temperatures in the range of about 50C to the boiling point of the reaction mixture. Advantageously, a small amount of a reaction initiator, suchas,

is proazo-bis-ibutryonitrile or'dibenzoyl peroxide, as well as a hydrogen halide acceptor, for example, pyridine, .triethylamine, collidine, allyl chloride, an epoxide or the like can F be added. A resulting 10,1 1-dihydro compound which is mono-halogenated in the lO- or 11- positionis-subsequently treated with a basic agent, such as sodium hydroxide, potassium carbonate, triethylamine, or the like, ata temperature in the range of about room temperature and the boiling point of the reaction mixture, whereby a 10,1 l-double bond is formed under cleavage of hydrogen halide. Resulting 10,1l-dihalogen-10,1l-dihydro compounds can be reacted with zinc in ether or dioxan. In this manner a 10,1l-double bond is also obtained. A protecting group bound to the nitrogen atom is then hydrolytically cleaved in the manner described hereinbefore and there results and amine of the formulas la or. lb, which is unsaturated in 10,1 l-position.

Resulting unsymmetrically substituted compounds of the formulas la or lb which carry an exocyclic double bond, as well their salts, can be separated into their geometric isomers i.e. aand ,B-isomers. The methods of separation are known per se. The geometric isomers are preferably separated by fractional crystallisation of the acid addition salts from a solvent, e.g. acetone, or r from a solvent mixture, e.g. methanol/diethyl ether.

Resulting unsymmetrically substituted exocyclically saturated compounds of the formulas la'or lb, as well as their salts, are obtained as racemates. They can be sep The compounds of formulas la and lb and their pharmaceutically acceptable acid'addition salts possess psychopharmacological antidepressant activity and are therefore useful as psychopharmacological antidepressants. Moreover, the compounds of formulas Ia and lb and their salts possess the advantage of being devoid of certain undesirable effects, for instance, they are substantially free of anticholinergic activity and have a very low toxicity. Additionally, the compounds of formulas Ia and lb and their salts have demonstrated narcosis potentiating, adrenolytic, sedative, antihistaminic and local anesthetic activities. Their useful psychopharmacological antidepressant activity is demonstrated in warm-blooded animals utilizing standard procedures. For example, groups comprising 10 mice each are administered the test substance in variable amounts subcutaneously. After 16 hours, they are given subcutaneously 5 mg/kg of 2-hydroxy-2-ethyl-3-isobutyl- 9,10-dimethoxy-1 ,2,3,4,6,7-hexahydro-l lbl-l-benzyl- [a]quinolizine (substance A), and 30 minutes thereafter, they are given 'intraperitoneally 3.75 mg/kg of ethanol. A control group of 10 animals is given only ethanol. The durationlof sleep is measured in all animals.

The percentage decrease in duration in sleep in comparison with the duration of the substance A potentiated sleep reflects the psychopharmacological antidepressant effect.

When 1 -chloro- 1 0,1 1 -dihydro--( 3 -methylaminopropyl)5H-dibenzo[a,d]cycloheptene, which has an LD of 700 mg/kg p.o., is utilized as the test substance at dosages in the range of 5-20 mg/kg sc., a corresponding 32-57 percent decrease in duration of sleep is produced.

When l-chloro-5-(3-dimethylaminopropylidene)- 5l-l-dibenzo[a,d] cycloheptene, which has an LD of 350 mg/kg p.o., is utilized as the test substance at dosages in the range of 2.5- mg/kg s.c., a corresponding 4881 percent decrease in duration of sleep is produced.

The substantial absence of anticholingeric effect is demonstrated in rabbits. Philocarpine is administered to urethanenarcotized rabbits and their saliva drippings are collected in a measuring cylinder over a period of minutes. Immediately thereafter, they are given 1,3 or 6 mg/kg iv. of the substance to be evaluated, and their saliva drippings are collected in a measuring cylinder over a period of 15 minutes. The saliva drippings of controls are also collected over two successive periods of 15 minutes each. The anticholinergic effect is reported as the percent inhibition of salivation taken in relation to the saliva production before the administration of the test substance. When the l-chloro-lO,l ldihydro-S 3-methylaminopropyl )-5 H-dibenzo [a,d] cycloheptene is administered in the range of l-6 mg/kg. i.v., a corresponding 5-19 percent inhibition of salivation is produced. This is much lower than the inhibition obtained with standard psychopharmacological antidepressants such as amitriptyline.

The compounds of formulas Ia and lb and their pharmaceutically acceptable acid addition salts have effects qualitatively similar to those of amitriptyline, known for its therapeutic uses and properties. Thus, the compounds of this invention demonstrate a pattern of activity associated with psychopharmacological antidepressants of known efiicacy and safety.

The compound of formulas Ia and lb can be used as medicaments, for example, in the form of pharmaceutical preparations which contain them or their salts in admixture with a pharmaceutical, organic or inorganic inert carrier material suited for enteral or parenteral application, such as, for example, water, gelatin, lactose, starch, magnesium stearate, talc, vegetable oils, gums, polyalkyleneglycols, and the like. The pharmaceutical preparations can be in solid form, for example,

tablets, dragees, suppositories, capsules, or in liquid form, for example, as solutions, parenteral solutions, suspensions or emulsions. They may be sterilized and may contain additives, such as preserving, stabilizing, wetting or emulsifying agents, salts for varying the osmotic pressure or buffers. They may also contain other therapeutically valuable substances.

A suitable pharmaceutical dosage unit contains from about 1 to 50 mg. of a compound of formula la or lb. Suitable oral dosage regimens in warm-blooded mammals falls within the range of from about 0.1 mg/kg per day to about 50 mg/kg per day. Suitable parenteral dosage regimens in warm-blooded mammals falls within the range of from about 0.01 mg/kg per day to about 10 mg/kg per day. However, for any particular subject, the

specific dosage regimen should be adjusted according to individual need and the professional judgement of the person administering or supervising the administration of a compound of formula Ia or lb.

The following non-limiting examples further illustrate the invention. All parts are by weight and all temperatures are in degrees centigrade, unless otherwise mentioned.

EXAMPLE 1 Preparation of l-chloro-10,1 l-dihydro-5-(3-dimethylarninopropyl)-5H-dibenzo[a,d]cycloheptene 500 g. of 1-chloro-10,l l dihydro-5-(3-dimethylaminopropyl)-5-hydroxy-5'H'dibenzo[a,d]cycloheptene, 437 g. of red phosphorus, 4,000 ml. of glacial acetic and 2,160 ml. of 57 percent hydroiodic acid are heated under reflux conditions in an atmosphere of argon for 3 hours. The resulting suspension is filtered. The filtrate is washed with 2,000 ml. of boiling water and subsequently cooled to 20. The crystals which form are separated by decantation and the mother liquor is concentrated under reduced pressure. The combined residues are suspended in 15,000 ml. of water. The suspension is cooled with ice and, with stirring, adjusted to pH 10-12 with concentrated caustic soda.

The solution is extracted with 4,000 ml. of methylene chloride. The resulting organic phase is successively washed with saturated sodium chloride solution and sodium thiosulfate solution, dried with sodium sulfate and evaporated under reduced pressure. The residue is dissolved in 2,000 ml. of ether. The ethereal solution is filtered, and the filtrate is evaporated to yield yellow, oily l-chloro- 10,1 1-dihydro-5-(3-dimethylaminopropyl)- 5l-l-dibenzo'[a,d]cycloheptene. The hydrochloride of this compound crystallizes from acetone/ether and has a melting point of l49l53.

The l-chlorol 0,1 1-dihydro-5-( 3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene employed as starting material can be prepared as follows:

86.6 g. of Gilman alloy or magnesium turnings are heated under reflux conditions in 800 ml. of absolute ether with a trace of iodine. Subsequently, a solution of 390 g. of dimethylaminopropyl chloride in 500 ml. of absolute tetrahydrofuran is added dropwise over a period of 2 hours. The resulting mixture is heated under reflux conditions for an additional 3 hours. To the suspension obtained previously cooled to 15C., there is added dropwise over a period of 15 minutes a solution of 242.7 g. of 1-chloro-10,ll-dihydro-5H-dibenzo[a,d- ]cyclohepten-S-one in 500 ml. of absolute tetrahydrofuran, and the resulting mixture is heated under reflux conditions for 12 hours. Thereafter, the reaction mixture is cooled to 15, hydrolyzed with 500 ml. of saturated ammonium chloride solution, filtered, and rinsed with methylene chloride. The filtrate is dried with sodium sulfate and evaporated under reduced pressure. The residual yellow substance is recrystallized from 6000 ml. of high-boiling petroleum ether to yield 1- chloro- 10, l l -dihydro- 5- 3-dimethylaminopropyl )-5- hydroxy-5H-dibenzo[a,d]cycloheptene, having a melting point of 13ll32.

EXAMPLE 2 Preparation of the a and B isomers of l-chlorol 0,1 l-dihydro--( 3-dimethylaminpropylidene)-5H-dibenzo[a,d]hydrochloride cloheptene hydrochloride, having a melting point of 208210. This compound represents a mixture of the two geometric isomers a ,B in the proportion of 1:1. The isomeric mixture is recrystallized from methanol/ether to yield the B-isomer which has a melting point of 222-225. The a-isomer crystallizes out from the mother liquor and has a melting point of 202-206.

EXAMPLE 3 Preparation of 1-chloro-5-( 3-dimethylaminopropylidene )-5H-dibenzo[ a,d]cycloheptene hydrochloride 10 g. of 1-chloro-5-(33-dimethylaminopropyl)-5- hydroxy-5H-dibenzo[a,d]cycloheptene are heated under reflux conditions for 1 hour in 50 ml. of absolute ethanol and l 1 ml. of 30 percent ethanolic hydrochloric acid. The mixture is evaporated under reduced pressure, taken up in water, washed with ether and made alkaline with 2N sodium hydroxide solution. This solution is shaken out with methylene chloride. The resulting organic phase is washed with water, dried with sodium sulfate and evaporated to yield l-chloro-5-(3- dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene hydrochloride as a viscous oil, having a melting point of 193-194. This compound represents a mixture of the a and B isomers in the proportion of about 1:1.

The enrichment of the B-isomer can be effected by recrystallization of the said hydrochloride from methanol/ether. A product containing 75 percent B-isomer has a melting point of 212-219, while a 94 percent product has a melting point of 2 16221. The aisomer is produced from the mother liquor as a 97.8 percent product having a melting point of 99-1l0'.

The l-chloro-5-(3-dimethylaminopropyl)-5- hydroxy-5l-l-dibenzo[a,d]cycloheptene employed as starting material can be prepared as follows:

17 g. of magnesium and 85 g. dimethylaminopropyl chloride are reacted utilizing the procedure of Example 1. The resulting Grignard compound is then treated with a solution of 52 g. of 1-chloro-5H-dibenzo[a,d]cyclohepten-S-one in 500 ml. of absolute tetrahydrofuran. Utilizing the work-up procedure of Example 1, there is obtained 1-chloro-5-(3-dimethylaminopropyl)- 5-hydroxy-5l-l-dibenzo[a,d]cycloheptene, having a melting point of 13414 136. The hydrochloride prepared therefrom has a melting point of 22'6227, after recrystallization from methanol/ether.

EXAMPLE 4 Preparation of l-chloro l 0,1 l-dihydro-5-( 3-methylaminopropylidene)-5H-dibenzocyclo[a,d]heptene hydrochloride A mixture of 20 g. of l-chloro-l0,l1-dihydro-5-(3- chloropropylidene)-5l-l-dibenzo[a,d]cycloheptene, m1. of absolute methanol and 30 g. of methylamine is heated in an autoclave for 12 hours at under a nitrogen pressure of 6 atmospheres. Subsequently, the solution is evaporated under reduced pressure and the resulting yellow, oily residue is treated with methanolic hydrochloric acid, whreby l-chloro-l0,1l-dihydro-S- (3-methylaminopropylidene )-5H-dibenzocyclo[ a,d- ]heptene hydrochloride separates out. After recrystallization from methanol/ether, this compound has a melting point of 2092l0, and comprises a mixture of the a and B-isomers in the proportion of about 3:2.

The l-chloro-l0,l l-dihydro 5-( 3-chloropropylidene)-5l-l-dibenzo[a,d]cycloheptene used as starting material can be prepared as follows:

To 14 g. of Gilman alloy in 100 ml. of absolute ether, after the addition of a trace of iodine or methyl iodide, there is added dropwise a solution of 45.6 g. of lchloro-3-methoxypropane in 300 ml. of absolute ether over a period of 30 minutes under reflux conditions. The reaction mixture is heated for an additional 3 hours. After cooling to 20, a solution of 48.5 g. of 1- chloro- 10,1 l-dihydro-S H-dibenzo[ a,d ]cyclohepten- 5-one in 1 60 ml. of tetrahydrofuran is added over a period of 30 minutes. This reaction mixture, after being heated under reflux conditions for 12 hours, is hydrolyzed with ml. of saturated ammonium chloride solution with cooling, filtered, rinsed with chloroform, dried with sodium sulfate and evaporated. The chlorol 0, l l -dihydro-5-( 3-methoxypropyl)-5- hydroxy-5H-dibenzo[a,d]cycloheptene obtained has a melting point of 80-8l, after recrystallization from ether/petroleum ether.

53.3 g. of l-chloro-l0,l1-dihydro-5-(3-methoxypropyl )-5-hydroxy-5H-dibenzo[ a,d] cycloheptene are heated under reflux conditions for 1, hour in 250 ml. of methanol and 53 ml. of 30 percent methanolic hydrochloric acid. Thereafter, the mixture is evaporated under reduced pressure, taken up in ether, washed with water, dried with sodium sulfate and reevaporated to yield 1 -chloro- 1 O, 1 l-dihydro-5-( 3-methoxypropylidene)-5H-dibenzo[a,d] cycloheptene as a yellow oil.

48.5 g. of 1-chloro-10,l l-dihydro-5-(3-methoxypropylidene)-5H-dibenzo[a,d]cycloheptene are dissolved in 150 ml. of methylene chloride. The resulting solution is cooled to 10 and treated over a period of 15 minutes with a solution of 30 g. of boron trichloride in 150 ml. of methylene chloride. The reaction mixture is stirred at room temperature for 19 hours, and thereafter it is poured on ice-water, extracted with methylene chloride, washed with water and dried over sodium sulfate. After evaporation, there is obtained l-chloro- 10,1 l-dihydro-5-( 3-chloropropylidene )-5 l-l-dibenzo[a,d]cycloheptene as a yellow-orange oil which slowly crystallizes out and has amelting point of 5153.

V EXAMPLE Preparation of l-chloro-5-( 3-methylaminopropylidene )-5H-dibenzo [a,d]cyc lohepte ne hydrochloride If the l-chlorol 0,1 l-dihydro-5- 3-chloropropylidene)-5H-dibenzo[a,d]cycloheptene of Example 4 is replaced by l-chloro- 5-(3-chloropropylidene)- 5l-l-dibenzo[a,d]cycloheptene, under otherwise similar conditions, there is obtained 1-chloro-5-( 3- methylaminopropylidene-5 H-dibenzo[a,d]cycloheptene hydrochloride. A mixture of the two aand ,B-isomers of this compound has a melting point of 208-2l6.

The l-chloro-5-( 3-chloropropylidene)-5H-dibenzo[a,d]cycloheptene employed as starting material for this reaction can be prepared as follows:

To 10.5 g. of Gilman alloy in 100 ml. of absolute ether, after the addition of a trace of iodine and l-3 drops of methyl iodide, there is added dropwise a solution of 34.1 g. of l-chloro-3-methoxypropane in 300 ml. of absolute ether over a period of 30 minutes under reflux conditions. After the addition of 150 ml. of tetrahydrofuran, the reaction mixture is heated for an additional 3 hours. Thereafter, it is cooled to and a solution of 36 g. of lchloro-5H-dibenzo[a,d]cyclohepten- 5 one in 300 ml. of tetrahydrofuran is added over a period of 15 minutes. This reaction mixture, after being heated under reflux conditions for 15 hours, is hydrolyzed with 150 ml. of saturated ammonium chloride solution with cooling, filtered, dried with sodium sulfate and evaporated under reduced pressure to yield 1- chloro-5-( 3-methoxypropyl )-5-hydroxy-5 H-dibenzo[a,d]cycloheptene as a yellow, viscous oil,

. 50 g. of 1-chloro-5-(3-methoxypropyl)-5-hydroxy- SH-dibenzo [a,d]cycloheptene are dissolved in 250 ml. of absolute methanol, heated under reflux conditions for 1 hour with 50 ml. of 30 percent methanolic hydrochloric acid, and subsequently concentrated under reduced pressure. The residue is taken up in ether, washed with water, dried with sodium sulfate and evaporated to yield l-chloro-5-(3-methoxypropylidene 5l-l-dibenzo[a,d]cycloheptene as a red oil.

42.8 g. of 1-chloro-5-(3-methoxypropylidene)-5H- dibenzo[a,d]cycloheptene are cooled to lO in 150 ml. of methylene chloride. A solution of 26.7 g. of boron trichloride in 150 ml. of methylene chloride is then added dropwise over a period of 15 minutes. The reaction mixture is stirred at room temperature for l9 hours. Subsequently, the mixture is poured on icewater, extracted with methylene chloride, washed with water and dried with sodium sulfate. The residue is taken up in benzene and purified by filtrationwith 300 g. of silica gel to yield l-chloro.-5-( 3-chloropropylidene)-5H-dibenzo[a,d]cycloheptene as a red oil which, after crystallization from petroleum ether, has a melting point of 53-60.

EXAMPLE 6 Preparation of l-chloro-5-( 3-dimethylaminopropyl)- SH-dibenzo[a,d]cycloheptene 5.6 g. of magnesium turnings are suspended in 100 ml. of absolute tetrahydrofuran and treated with a trace of iodine and methyliodide. To this mixture there is added dropwise a solution of 26 g. of dimethylaminopropyl chloride in 100 m1. of tetrahydrofuran over a period of about 20 minutes under reflux conditions. The mixture is boiled for an additional 3 hours. After cooling the mixture to 20, a solution of 25.2 g. of 1,5- dichloro-5H-dibenzo[a,d]cyc'loheptene in 250 ml. of tetrahydrofuran is added dropwise over a period of 15 minutes. The mixture is subsequently heated under reflux conditions for 15 hours, cooled and hydrolyzed with 200 ml. of saturated ammonium chloride solution. The resulting mixture is filtered and rinsed with methylene chloride. The filtrate is dried with sodium sulfate and evaporated under reduced pressure to yield 1- chloro-5-(3-dimethylaminopropyl)-5H-dibenzo[a,d- ]cycloheptene as a viscous oil which has a boiling point of about l60/0.01 mm.

EXAMPLE 7 Preparation of l-chloro- 10, 1 l-dihydro-5-( 3-:methylaminopropyl )-5 H- dibenzo[a,d]cycloheptene hydrochloride A solution of 102.5 g. of ll-chloro-l0,l l-dihydro-S- (3-dimethylaminopropyl)-5l-1=dibenzo[a,d]cycloheptene in 500 ml. of methylene chloride is addeddropwise to a solution of 55 g. of cyanogen bromide in 500 ml. of methylene chloride. The reaction mixture is stirred at room temperature for 12 hours and subsequently poured on ice-water. The methylene chloride phase is washed with 2N hydrochloric acid and water, dried with sodium sulfate and evaporated under reduced pressure. The residue obtained is a yellow oil which is crystallized from ether to yield l-chlorol 0, l l -dihydro-5-( 3-N-cyano-N-methylaminopropyl 5l-l-dibenzo[a,d]cycloheptene, having a melting point of 69-7 1 After being dissolved in benzene/ether, this compound can be chromatographically purified on 500 g. of silica gel.

A mixture of 650 g. of l-chl oro-IOJ l-dihydro-5-(3- N-cyano-N-methylaminopiopy1)-5H-dibenzo[a,d]cycloheptene, 4,000 ml. of glacial acetic, 2,000 ml. of water and 1,000 ml. of concentrated hydrochloric acid are heated under reflux conditions for 24 hours. The reaction mixture is concentrated under reduced pressure, diluted with 20,0002tnl1. of ice-cold water and wahsed with 5,000 ml. of methylene chloride. The mixture is made alkaline with: a concentrated sodium hydroxide solution and the resulting precipitation is taken up in methylene chloride. Following concentration of the methylene chloride solution, there is obtained a brown-red oil which is converted into the crystalline EXAMPLE 8 Preparation of l-chloro-5-(3-methylaminopropylidene)-5H-dibenzo[a,d]cycloheptene A solution of 5.4 g. of l-chl-oro-5-( 3-dimethylaminopropylidene)-5ll-dibenzo[a,d]cycloheptene hydro- 23 chloride is added dropwise to a solution of 2.1 g. of cyanogen bromide in 20 ml. of methylene chloride. The reaction mixture is stirred at room temperature for 20 hours and subsequently washed with water, 2N hydrochloric acid and water, dried with sodium sulfate and evaporated to yield 1-chloro-5-( 3 -N-cyan-N.

methylaminopropylidene)-5l-l-dibenzo[ a,d]cycloheptene as a yellow oil which is dissolved in benzene and chromatographically purified on 50 g. .of silica gel. A mixture of 4.4 g. of l-chloro-5-(3-N-cyano-N- methylaminopropylidene)-5Hdibenzo[a,d]cyclohep- EXAMPLE 9-" v v Preparation ,of {flubr'o-l 0, l l-dihydro-5-( S-dirnethylaminofpropylidene)-5H dibenzo[a,d-]cycloheptene v .l 5 g.; '0fj,lefluoro-l0,1 1 dihydro-'5 (3-dimethylamino propyl)-5rhydroxy-5H-dibenzo[a,d]cycloheptene are heated under reflux conditions for 2 hours with 100 ml.

of absolute ethanol and 12 ml.'of 30percent ethanolic hydrochloric acid. The resulting reaction mixture is evaporated under-reduced pressure, and is worked up in the manner setforth in Example 1 to yield 1-fluorol0, 1'1'-dihyd ro-5-( 3-dimethylaminopropylidene )-5H- dibenzo[a,d] cycloheptene, the hydrochloride of which has a melting point of l87200 after recrystallization from methanol/ether. The compound comprises a mixture of the aand B-isomers.

The l-fluorol 0,1 l-dihydro-5-( 3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene employed as starting material can be prepared as follows:

' 14.8 g of pulverised phthalic anhydride, 18.5 g of orthofluorophenyl acetic acid'and 0.5 g of freshly melted sodium acetate are heated for 3 hours at 235-240C and the resulting water is distilled off. The hot reaction mixture is transfered into a mortar and pulverised. The crude product is recrystallised from acetone/petroleum ether. There is obtained ortho-fluorobenzylidene phthalide, which melts at l48l5lC.

. 72.6 g of ortho-fluorobenzylidene phthalide are heated 'in an argon atmosphere for 24 hours under reflux'conditions together with 55.0 g of red phosphorus and 450 ml of hydroiodic acid (density 1.75 The reaction mixture is cooled, supplied with 500 ml of water and filtered. The residue is heated with 2N caustic soda to 80C and again filtered to remove the phosphorus. The alkaline solution is acidified and extracted with methylene chloride, washed with water, dried and evaporated to dryness. The crude product obtained is recrystallised from acetone/low boiling petroleum ether 2-(ortho-Fluorophenethyl)-benzoic acid is obtained as white crystals melting at 9394C.

280 g of poly-phosphoric acid are heated to C and, in an atmosphere of argon, 70.0 g of 2-(orthofluorophenethyl)-benzoic acid are added. The heating is continued over a hour period at 15,0C, the reaction mixture is poured over ice waterand extracted with ether. The ether extract is washed with water, 2N caustic soda and again with water until neutral, dried over sodium sulphate, filtered and evaporated to dryness. The residual, crude product is distilled under reduced pressure. There is obtained l-fluoro-10,l l-dihydro- 5l-I-dibenzo[a,d]cycloheptene-5-one as a yellow oil which crystallises upon standing, mp. 6465C.

19.1 g. of Gilman alloy and a trace of iodine are suspended in ml. of absolute ether, and are reacted with 88 g. of dimethylaminopropyl chloride in 200 m1. of tetrahydrofuran as in Example 1. To the resulting suspension thereis added dropwise at 20 a solution of 50 g. of 1-fluoro.-1 0,l l-dihydro-SH-dibenzo [a,d]cyclohepten-S-one in250 ml. of tetrahydrofuran over a 1-hour period. The reaction mixture is heated under reflux conditions for 15 hours and, after cooling, .is hydrolyzed with saturated ammonium chloride solution. The resulting reaction mixture is filtered, rinsed with methylene chloride, dried with sodiumsulfate and evaporated under reduced pressure to yield l-fluoro- 10, l 1-dihydro-5-(3-dimethylaminopropyl)-5-hydroxy- SH-diberizo[a,d]cycloheptene 'which, after crystallization from-high-boiling petroleum ether, has a melting point of 1l5l17. .1 I I 15 g. of 1-fluoro-10,1 l-dihydro-5-( 3-dimethylamino- "propyl)-5-hydroxy-5l-l-dibenzo[a,d]cycloheptene are heated under reflux conditions for 3 hours in an atmosphere of argon with 14g. of red phosphorus, 250 g. of glacial acetic and 70 ml. of 57 percent hydroiodic acid. Thereafter, the mixture is filtered hot and the filtrate is concentrated under reduced pressure. The residue is treated with 2N sodium hydroxide solution and is taken up in methylene chloride. The greenish oil which forms is then purified by chromatography in benzene solution on the 20-fold amount of aluminum oxide to yield 1- fluorol O 1 1 -dihydro-5 3-dimethylaminopropyl )-5 H- dibenzo[a,d]cycloheptene, the hydrochloride of which has a melting point of l69-170, after recrystallization from methanol/ether.

EXAMPLE 11 Preparation of the aand fi-isbmers of l-chloro-lO (or 1 l )-bromo-5-( 3-dimethylaminopropylidene)-5H- dibenzo[a,d]cycloheptene hydrochloride 11.9 g. of l-chloro-lO (or ll)-bromo-5-(3-dimethylaminopropyl)-5-hydroxy-5l-l-dibenzo[a,d]cyclohepte ne .are-heated u nder reflux conditions for 15 hours in 100 ml. of 32 percent ethanolic hydrochloric acid. The reaction mixture is concentrated under reduced pressure, whereby there is obtained a mixture consisting of the aand fl-isomers of l-chloro-lO (or 1 l )-bromo-5-( 3-dimethylaminopropylidene )-5H- dibenzo[a,d]cycloheptene hydrochloride. This mixture is dissolved in water, made alkaline by the addition of 2N sodium hydroxide solution and extracted with chloroform. The chloroform extract is dried with sodium sulfate, filtered and evaporated. The resulting residue is 10 dissolved in benzene and filtered on the 30-fold amount of aluminum oxide (activity grade II). The filtrate is evaporated, acidified with rnethanolic hydrochloric acid and reevaporated. The residue is treated with acetone, whereby l-chloro-lO (or l1)-bromo-5-(3-dimethylaminopropylidene )-5H -dibenzo[ a,d] cycloheptene hydrochloride which has a melting point of 221-224 and consists of 96.5 percent a-isomer and 3.5 percent ,B-isomer which crystallizes out. The B-isomer can be obtained from the mother liquor. 1

The l-c hlorol (or 1 l )-bromo--( 3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene employed as starting material can be prepared as follows:

21.3 g. of l-chloro-5H-dibenzo[a,d]cyclohepten -5-one are suspended in 200 ml. of carbon tetrachloride. The resulting mixture is treated over a period of about 45 minutes with a solution of 14 g. of bromine in 40 ml. of carbon tetrachloride. At the same time, the reaction mixture is irradiated with a 500 W lamp. After complete addition, the reaction mixture is irradiated for an additional 30 minutes. Subsequently, it is stirred for 12 hours and then filtered. The recovered fine precipitate is washed with petroleum ether and dried under reduced pressure. The l-chloro-l0,l l-dibromo- 10, 1 l-dihydro-S l-l-dibenzo a,d ]cyclohepten-S-one obtained (which melts at l69-170 with decomposition) is immediately suspended in 300 ml of ethanol, treated with a solution of 5.5 g of potassium hydroxide in ml of water and heated under reflux conditions for 4 hours. The reaction mixture is evaporated to dryness under reduced pressure, taken up in ether, washed with water and dried with sodium sulfate. The dried ethereal solution is concentrated to 500m]. to yield crystalline l-chlorol 0 (or 1 1 )-bromo-5H-dibenzo[a,d]cyclohepten-S-one, having a melting point of l25127, after recrystallization from ethanol.

2.76 g. of Gilman alloy are heated in 10 ml. of absolute ether with a trace of iodine and a few drops of methyl iodide. A solution of 10.5 g. of dimethylaminopropyl chloride in 50 ml. of absolute tetrahydrofuran is added dropwise over a period of 1 hour. The resulting mixture is heated under reflux conditions for 1 hour. To the suspension obtained previously cooled to 05, there is added dropwise over a period of 40 minutes a solution of 17.3 g. of l-chloro-lO (or l1)-bromo 5l-ldibenzo[a,d]cyclohepten-S-one in 100 ml. of absolute tetrahydrofuran. This mixture is heated under reflux conditions for 3 hours. Thereafter, the reaction mixture is hydrolyzed with 20 ml. of saturated ammonium chloride solution with cooling and is filtered. The residue is rinsed with ether. The combined filtrates are dried with sodium sulfate and evaporated to yield l-chloro-10 (or 1 l )-bromo-5-(3-dimethylaminopropyl)-5-hydroxy 5H- dibenzo[a,d]cycloheptene, having a melting point of EXAMPLE 1 2 Preparation of the 01- and B-isomers of 1,10 (or 1 1 )-dichloro-5-( 3-dimethylaminopropylidene)-5H- dibenzo[a,d]cycloheptene hydrochloride 25 g. of 1,10 (or ll)-dichloro-5-(3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene are heated under reflux conditions for 15 hours with ml. of absolute ethanol and ml. of 30 percent ethanolic hydrochloric acid. The reaction mixture is concentrated under reduced pressure. The residue is dissolved in water, made alkaline with 2N sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extract is washed with water, dried with sodium sulfate and evaporated to yield 1,10 (or 1 l )-dichloro-5-(3-dimethylaminopropylidene)-5 H- dibenzo[a,d]cycloheptene as a yellow oil. For purification, this oil is taken up in benzene and filtered on 200 g. of aluminum oxide. The product obtained represents a mixture of the aand ,B-isomers in the proportion of about 1:1. By conversion of this. product into the corresponding hydrochloride and recrystallization from acetone, there first separates out a product having a melting point of 222-224, which comprises 94 percent of the a-isomer and 6 percent of the ,B-isomer of 1,10 (or 1 l )-dichloro-5-(3-dimethylaminopropylidene)-5l-ldibenzo[a,d]cycloheptene hydrochloride. From the mother liquor there is obtained a product having a melting point of l32l40 and which consists of 17 percent a-isomer and 83 percent B-isomer. A further enrichment of the B-isomer is possible by repeated crystallizations. v v

The 1,10 (or ll)-dichloro-5-(3-dimethylaminopropyl)-5-hydroxy-5l-l-dibenzo[a,d]cycloheptene employed as starting material can be prepared as follows:

51.6 g. of l-chloro-5H-dibenzo[a,d]cyclohepten- 5-one are dissolved in 300 ml. of carbon tetrachloride. With heating at about 60 and irradiation with a 500 W lamp, an 18 percent (weight for volume) solution of chlorine in carbon tetrachloride is added dropwise over a period of 10 minutes. The reaction mixture is irradiated for an additional 10 minutes and subsequently cooled. The l 10, 1 l-trichloro- 1 0,1 l-dihydro-SH- dibenzo[a,d]cyclohepten-S-one which crystallizes out is removed by filtration, dried, immediately dissolved in 760 ml. of ethanol and treated with 33 g. of potassium carbonate and 30 ml. of water. This mixture is heated under reflux conditions for 8 hours. The crystals which separate out on cooling are removed by filtration and taken up in chloroform. The chloroform solution is washed with water, dried, filtered and evaporated. After recrystallization from ethanol, the residue yields 1,10 (or 1 l )-dichloro-5l-l-dibenzo[ a,d]cyclohepten- 5-one as long needles having a melting point of 143-145 6.04 g. of Gilman alloy are heated in 20 ml. of absolute ether with a trace of iodine and a drop of methyl iodide and a solution of 21.9 g. of dimethylaminopropyl chloride in 100 ml. of absolute tetrahydrofuran is subsequently slowly added dropwise. The reaction mixture is heated at 50 for 2 hours. After cooling to 0, a solution of 33 g. of 1,10 (or 1 l )-dichloro-5H- dibenzo[a,d-

]cyclohepten-S-one in 200 ml. of absolute tetrahydrofuran is added dropwise over a period of 15 minutes. This reaction mixture is heated under reflux conditions for 3 hours, cooled to treated with 100 ml. of a cold saturated ammonium chloride solution and filtered. The residue is rinsed with ether. The combined filtrates are dried with sodium sulfate, filtered and evaporated under reduced pressure. After recrystallization from high-boiling petroleum ether, the residue yields 1,10 (or l 1)-dichloro-5-( 3-dimethylaminopropyl hydroxy-SH-dibenzo[a,d]cycloheptene, having a melting point of 9294.

EXAMPLE 13 Preparation of the aand B-isomers of 1 ,3-dichloro-10, l 1-dihydro-5-( 3-dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene hydrochloride 25 g. of thylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene are heated with 250 ml. of 30 percent ethanolic hydrochloric acid under reflux conditions over a .15-hour period. After evaporation under reduced pressure, the reaction mixture is dissolved in water, washed with'ether and made alkaline with dilute sodium hydroxide solution. After extraction by shaking with ether and evaporation to dryness, the remaining oily mixtures of the isomers of l,3-dichloro-l0,1 1-dihydro-5-(3- dimethylaminopropylidene)-5H-dibenzo[a,d]cycloheptene by. treatment with a methanolic hydrochloric acid is converted to the hydrochloride. Following the recrystallization from acetone, the hydrochloride of the a-isomer precipitates, which has a melting point of 23 l233. From the mother liquors one obtains through crystallization from methanol/ether a product which is 94 percent of the hydrochloride of the B-isomer, having a melting point of 180183.

The starting material 1,3-dichloro-l0,1l-dihydro-S- 3-dimethylaminopropyl )-5-hydroxy-5H-dibenzo[ a,d- ]cycloheptene can be prepared as follows:

50 g. of 2-(2,4-dichlorophenethyl)-benzoate and 100 ml. of thionylchloride are heated together under reflux conditions over a 4-hour period. Following concentration under reduced pressure, the resulting acid chloride is dissolved in 500 ml. of carbon disulfide and is added dropwise to a boiling suspension of 70 g. of aluminum chloride in 1 1. carbon disulfide. After boiling for 4 hours, the reaction mixture is evaporated under reduced pressure, hydrolyzed with ice and extracted with ether, with water and 2N sodium hydroxide solution, and washed with water, dried and evaporated. The crude 1,3-dichloro- 10,1 l-dihydro-5H-dibenzo[a,dlcyclohepten-S-one is separated by chromatography on 300 g. of silica gel in benzene. The product has a melting point of lO8-1 10. Through the utilization of 2.9 g. of Gilman alloy, 13.5 g. of dimethylaminopropyl .chloride and 18 g. of l,3-dichloro-l0,l l-dihydro-Sl-l-dibenzo[a,d]cyclohepten-S-one, in accordance with the procedure set forth in Example 1, there is obtained 1,3-

dichloro- 10, 1 l-dihydro-5-( 3-dimethylaminopropyl )-5- 1 hydroxy-5H-dibenzo[a,d]cycloheptene, which is then immediately reacted further.

1 ,3-dichloro-10,1 l-dihydro-5-( 3-dime- 5 EXAMPLE 14 Preparation of 1,3-dichloro-10,1 1-dihydro-5-( B-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene hydrochloride 23.5 g. of 1,3-dichloro-10,1l dihydro-5-(3-dimethylaminopropyl)-5H-hydroxy-5H-dibenzo[a,d]cycloheptene'are mixed with 19 g. of red phosphorus, 320 ml. of glacial acetic acid and ml. of hydroiodic acid (having a specific gravity of 1.75), and the reaction mixture is heated for 4 hours at 1 15 in an atmosphere of argon. Whereupon, the reaction mixture is filtered hot. While cooling, the hydroiodide of 1,3-dichloro- 10,1 l-dihydro-5-( 3-dimethylaminopropyl)-5H-dibenzo[a,d]cycloheptene separates out and is taken up in water. Through the addition of 2N sodium hydroxide solution, the base separates out and is taken up in methylene chloride. And, after washing with water, is dried with sodium sulfate, filtered and evaporated. The residue is a yellow oil, which through the addition of ethanolic hydrochloric acid and ether separates out as the crystalline hydrochloride of 1,3-dichloro- 10,1 1dihydro-5-( 3-dimethylaminopropyl )-5 H-diben zo[a,d]cycloheptene. The product is hydroscopic and melts at 168169.

EXAMPLE 15 Preparation of 1 ,9-dichlorol 0,1 l-dihydro-5-( 3-dimethylaminopropylidene )-5H-dibenzo[a,d]cycloheptene 4.1 g. of 1,9-dichloro-l0,1 1-dihydro-5-(3-dime thylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene are heated in 100 ml. of 30 percent ethanolic hydrochloric acid under reflux conditions for 2 hours. After evaporation under reduced pressure, the residue is dissolved in water, washed with ether and made alkaline with sodium hydroxide solution and taken up in ether. Following evaporation of the ethereal residue, the oily 1,9-dichloro-10,11-dihydro-5-(3- dimethylaminopropylidene)-5l-l-dibenzo [a,d]cycloheptene is dissolved in benzene, purified by filtration with 50 g. of aluminum oxide and converted to the hydrochloride which after recrystallization from methanol/ether has a melting point of 234235.

The starting material 1,9-dichloro-10,1l-dihydro-S- (3-dimethylarninopropyl)-5-hydroxy-5H-dibenzo[a,d- ]cycloheptene can be prepared as follows:

18.2 g. of 3-chloro-phthalic anhydride and 20.5 g. of (2-chlorophenyl) acetic acid are melted with 0.5 g. of sodium acetate. The molten mass is poured into ml. of ethanol with stirring, cooled and filtered. The resulting mixture of the isomers "4-chloro-3-(2- chlorobenzylidene)-phthalide (A) and 7-chloro-3-(2- chlorobenzylidene)-phthalide (B) has a melting point of 159190. The separation of the isomers is accomplished through recrystallization from acetone. The desired isomer (A) precipitates in over 96 percent purity and has a melting point of 204-209. 53 g. of the resulting isomer (A) in 300 ml. of hydroiodic acid of specific gravity 1.75 are heated together with 40 g. of red phosphorus over av 24 -hour period in an atmosphere of argon under reflux conditions. The reaction mixture is added to 400 ml. of water, following cooling, filtered and washed with water. The residue is dissolved in hot 2N sodium hydroxide solution, and the solution is again filtered to remove the residual phosphorus. The filtrate is acidified with concentrated hydrochloric acid and is extracted with methylene chloride. The methylene chloride extract is washed with water, dried with sodium sulfate and evaporated. The resulting 4-ch1oro-3- (2-chlorobenzyl)-phthalide, after recrystallization from acetone/low boiling petroleum ether, has a melting point of l29130. 32.5 g. of 4-chloro-(2-chloroben- 2yl)-phthalide are dissolved in a solution of 14 g. of potassium hydroxide in 350 ml. of water. Following concentration of the reaction mixture under reduced pressure, potassium-[ 3-chloro-2-( 2-chloro-a-hydroxyphenethyl)-benzoate] is obtained as a solid foam. 48.6 g. of potassium ['3-chloro-2-( 2-chloro-a-hydroxyphenethyl)-benzoate] are dissolved in 100 and 300 ml. of dimethylsulfoxide and heated at 170 for 3 /2 hours in an atmosphere of argon. The reaction product is poured over ice-water and the entire mixture is acidified with 2N hydrochloric acid and extracted with methylene chloride. The methylene chloride extract is washed with water, dried with sodium sulfate and concentrated to yield 3-chloro-2-(2-chlorostyryl)-benzoate, having a melting point of 150l55.

15 g. of 3-chloro-(2-chlorostyryl)-benzoate are dissolved in 250 ml. of hydroiodic acid having a specific gravity of 1.75 and are agitated with 12 g. of red phosphorus over a 24*hour period at 125. The reaction mixture is thereafter mixed with 200 m1. of water and filtered. The residue is dissolved in 50 percent sodium hydroxide solution with warming. Following filtration of the phosphorus residue, the solution is washed with ether, acidified with concentrated hydrochloric acid and extracted with methylene chloride. The methylene chloride extract is dried with sodium sulfate and evaporated to yield 3-chloro-2-(2-chlorophenethyl)-benzoate, having a melting point of 137l39.

50 g. of polyphosphoric acid are heated to 120, and, in an atmosphere of argon, 7 g. of 3-chloro-2-(2- chloro-phenethyl)-benzoate are added. The heating is continued over a -hour period at 150. The reaction mixture is poured over ice and extracted with benzene. The benzene extract is washed first with 2N sodium hydroxide solution and then with water, dried over sodium sulfate and evaporated to yield 1,9-dichloro- 10,1 l-dihydro-5l-l-dibenzo[a,d]cyclohepten-5-one, which after recrystallization from acetone/low boiling petroleum ether has a melting point of 185-l87.

Through the utilization of 1.1 g. of Gilman alloy, 5.3 g. of dimethylaminopropyl chloride and 3.4 g. of 1,9- dichloro- 1 0, l 1-dihydro-5H-dibenzo[a,d] cyclohepten- 5-one, one obtains, according to the procedure of Example 1 1 ,9-dichloro-10,1 1-dihydro-5-( 3-dimethylaminopropyl)-5-hydroxy-5H-dibenzo[a,d]cycloheptene as a yellow oil, which is then immediately reacted further.

EXAMPLE 16 Tablets are prepared utilizing the following composition:

lchloro- 10,1 1-dihydro-5-( 3 methylaminopropyl)-5H-dibenzo[a,d]cycloheptene hydrochloride 28.05 g. Lactose g. Maize starch 57.95 g. Talcum 3.40 g. Magnesium stearate 0.6 g.

The ingredients are mixed together and compressed into tablets of 200 mg. each. Subsequently, they are coated with ethyl cellulose and Carbowax.

EXAMPLE 17 Tablets are prepared utilizing the following composition:

1-chloro5-( 3dimethylaminop ropylidene 5H-clibenzo[a,d]cycloheptene hydrochloride 28.05 g. Lactose 1 10 g. Maize starch 57.95 g. Talcum 3.40 g. Magnesium stearate 0.6 g.

The ingredients are mixed together and compressed into tablets of 200 mg. each. Subsequently, they are coated with ethyl cellulose and Carbowax.

We claim:

1. A compound of the formula wherein R is chlorine or fluorine, R and R are hydrogen, chlorine or fluorine, X is ethylene or vinylene and D is lower alkanoyl, phenyl-(lower alkanoyl), lower alkylsulfonyl, phenylsulfonyl, lower alkylphenylsulfonyl, phenyl-(lower alkyl)-sulfonyl, lower carbalkoxy, carbophenoxy or lower carbophenylalkoxy.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION PATENT NO. 3,917, 9 DATED November4, 1975 |NVENTOR(S) Emilio Kyburz & Hans Spiegelberg It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Cover Sheet after [60] Related U .8. Application Data" insert:

[30] Foreign Application Priority Data November 8 1966 Switzerland 16144/ 66 February 2 1967 Switzerland 1651/67 Signed and Scaled this A lres t:

RUTH C. MA SON C. MARSHALL DANN Arresting Offrcer Commissioner of Patents and Trademarks 

1. A COMPOUND OF THE FORMULA 